The present invention relates to substituted tetrahydropyrrolopyrazine compounds, processes for their preparation, pharmaceutical compositions comprising these compounds and the use of these compounds for the treatment and/or inhibition of pain.
The treatment of pain, in particular neuropathic pain, is of great importance in medicine. There is a worldwide need for effective pain therapies. The longstanding need for a target-orientated treatment of chronic and non-chronic states of pain appropriate for the patient, by which is to be understood successful and satisfactory pain treatment for the patient, is also documented in the large number of scientific works which have been published in the field of applied analgesics and of fundamental research into nociception.
A pathophysiological feature of chronic pain is the overexcitability of neurons. Neuronal excitability is influenced decisively by the activity of K+ channels, since these determine decisively the resting membrane potential of the cell and therefore the excitability threshold. Heteromeric K+ channels of the molecular subtype KCNQ2/3 (Kv7.2/7.3) are expressed in neurons of various regions of the central (hippocampus, amygdala) and peripheral (dorsal root ganglia) nervous system and regulate the excitability thereof. Activation of KCNQ2/3 K+ channels leads to a hyperpolarization of the cell membrane and, accompanying this, to a decrease in the electrical excitability of these neurons. KCNQ2/3-expressing neurons of the dorsal root ganglia are involved in the transmission of nociceptive stimuli from the periphery into the spinal marrow (Passmore et al., J. Neurosci. 2003; 23(18): 7227-36). It has accordingly been possible to detect an analgesic activity in preclinical neuropathy and inflammatory pain models for the KCNQ2/3 agonist retigabine (Blackburn-Munro and Jensen, Eur J Pharmacol 2003; 460(2-3); 109-16; post et al., Naunyn Schmiedebergs Arch Pharmacol 2004; 369(4): 382-390). The KCNQ2/3 K+ channel thus represents a suitable starting point for the treatment of pain; in particular pain chosen from the group consisting of chronic pain, neuropathic pain, inflammatory pain and muscular pain (Nielsen et al., Eur J. Pharmacol. 2004; 487(1-3): 93-103), in particular neuropathic and inflammatory pain.
Moreover, the KCNQ2/3 K+ channel is a suitable target for therapy of a large number of further diseases, such as, for example, migraine (US2002/0128277), cognitive diseases (Gribkoff, Expert Opin Ther Targets 2003; 7(6): 737-748), anxiety states (Korsgaard et al., J Pharmacol Exp Ther. 2005, 14(1): 282-92), epilepsy (Wickenden et al., Expert Opin Ther Pat 2004; 14(4): 457-469) and urinary incontinence (Streng et al., J Urol 2004; 172: 2054-2058).
Substituted tetrahydropyrrolopyrazines are known from the literature and from databanks. Thus, U.S. Pat. No. 4,188,389 discloses tetrahydropyrrolopyrazines which are suitable for treatment of depression. WO 94/29315 discloses tetrahydropyrrolopyrazines having anxiolytic properties, which are unsubstituted on the piperazine ring except for on the piperazine nitrogen. WO 2003/024967 discloses tetrahydropyrrolopyrazines which carry a (C═Z)-NH2 substituent on R3 and are suitable for treatment of cancer. Tetrahydropyrrolopyrazines are furthermore listed in databanks, for example at CAS, without any biological activity being mentioned.